Human Endometrial Regenerative Cells Attenuate Bleomycin-Induced Pulmonary Fibrosis in Mice.

Yiming Zhao,Xiaoxi Xu,Baoren Zhang,Shanzheng Lu,Hao Wang,Caigan Du,Ganggang Shi,Yong Wang,Xiangying Gu,Xu Lan,Xiang Li

doi:10.1155/2018/3475137

Abstract

Endometrial regenerative cells (ERCs) have been recently evaluated as an attractive novel type of stem cell therapy. Previous studies have demonstrated that most ERCs accumulated in the lung after injection and are successfully used to treat diseases such as cardiac fibrosis. However, relevant studies of ERCs in idiopathic pulmonary fibrosis (IPF) have not been reported. The present study was designed to examine the effects of ERCs on bleomycin-induced pulmonary fibrosis. All IPF models in C57BL/6 mice were induced by administrating 5 mg/kg bleomycin in PBS intratracheally. ERCs were isolated from healthy female menstrual blood and were injected (1 million/mouse, i.v.) 24 hours after induction. Wet/dry weight ratio assay, hydroxyproline content, pathological and immunohistological changes, MDA content, T-SOD activity, cytokine profiles, and RT-qPCR analysis were assessed 2 weeks after disease induction. The results showed that ERC treatment significantly decreased the wet/dry ratio and reduced collagen deposition. Histological analyses, Masson staining, and hydroxyproline content analysis indicated that ERCs could reduce collagen fiber production. Immunohistochemical staining revealed lower expression of TGF-β after ERC treatment. Furthermore, mice treated with ERCs had lower levels of IL-1β and TNF-α, but a higher level of IL-10 in both the lung and serum. Gene expression analysis demonstrated that ERCs potently suppressed the proapoptotic gene Bax, while increasing the antiapoptotic gene Bcl-2 and antifibrosis genes HGF and MMP-9. Our results indicate that human ERCs protected the lung from pulmonary fibrosis in mice through immunosuppressive and antifibrosis effects. Moreover, these findings formed a foundation for the further use of ERCs in clinical treatment.

Highlights

Idiopathic pulmonary fibrosis (IPF), the most common form of the idiopathic interstitial pneumonias, is a chronic, progressive, irreversible, and usually lethal lung disease of unknown cause [1]
It has been observed that on-going AEC injury in the lungs and aberrant repair mechanisms have been implicated in the pathogenesis of IPF
We have investigated whether human Endometrial regenerative cells (ERCs) have therapeutic effects on inhibiting pulmonary fibrosis in a mouse model and found that the lung in the untreated group became inflamed and mauve and had fibrous deposition under macrography (Figure 1(a)), suggesting that bleomycin had induced severe pulmonary fibrosis

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF), the most common form of the idiopathic interstitial pneumonias, is a chronic, progressive, irreversible, and usually lethal lung disease of unknown cause [1]. A recently held theory about the pathophysiology of IPF suggested association with oxidative stress, hyperplasia, Stem Cells International denudation, and apoptosis of type II alveolar epithelial cells (AEC II) might be a primary cause of this process [4, 5]. TGF-β plays a central role through inducing myofibroblast accumulation, enhancing extracellular matrix synthesis, and promoting the epithelial mesenchymal transition (EMT) [8, 9]. Two drugs, pirfenidone and nintedanib, were approved by the FDA for clinical use as they were able to slow down the disease progression. Pirfenidone is an antifibrotic, anti-inflammatory, and antioxidant molecule which inhibits TGF-β-induced collagen synthesis [10, 11]

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